Novel pharmaceutical compositions of anti-tubercular drugs and process for their preparation

ABSTRACT

A pharmaceutical composition of anti-tubercular drugs for oral use comprising Rifampicin and/or Isoniazid wherein the bioavailability of Rifampicin and/or other drugs is enhanced. Preferably the bioavailability of Rifampicin is enhanced by preventing its degradation caused by presence of Isoniazid. Rifampicin and/or Isoniazid may be present in delayed release and/or extended release form such that minimal amount of the drug is dissolved between pH 1 and 4. preferably delayed release of Rifampicin and/or Isoniazid is achieved by treating the drugs with pH sensitive polymers.

[0001] Tuberculosis is a major problem largely of developing countriesbut lately emergence of Mycobacterium infections in HIV infectedindividuals is also on the rise in developed countries. The managementof tuberculosis treatment is further complicated due to emergence ofdrug resistance. Drug resistance in tuberculosis is due to inappropriateprescribing or taking of medications, effectively resulting inmonotherapy. To reduce the possibility of monotherapy, the World HealthOrganization (WHO) and the International Union Against Tuberculosis andLung Diseases (IUATLD) have recommended that antitubercular drugs shouldbe taken in combination (Fixed dose combination tablets for thetreatment of tuberculosis, Report of an informal meeting held in GenevaApr. 27, 1999, World Health Organization Communicable Diseases Cluster,1999). A number of combinations of first line drugs containingrifampicin isoniazid pyrazinamide and ethambutol are in use This fixeddose combination (FDC) tablets provide a simple approach to deliveringthe correct number of drugs at the correct dosage as all the necessarydrugs are combined in a single tablet. By altering the number of pillsaccording to the patient's body weight, complete treatment is deliveredwithout the need for calculation of dose. However, such FDC tablets arenot free from disadvantages. The major issue is the adverse effect onbioavailability of rifampicin in presence of other drugs. Variousresearchers have worked on several aspects of this problem of FDCtablets and several recommendations are recorded in literature. WHOattributes that when rifampicin combined with the other drugs within thesame formulation the bioavailability negatively affected if themanufacturing procedures are not strictly controlled. Against thisbackground, WHO and IUATLD issued a joint statement in 1994 advisingthat only FDC tablets of good quality and proven bioavailability ofrifampicin should be used in the treatment of tuberculosis (Anonymous;1994; Tuber. Lung Dis.; 75: 180-181). There are several forthcomingarticles in a special supplement of the International Journal ofTuberculosis and Lung disease devoted to the quality assurance of FDCtablets. These include a simplified protocol for assessing rifampicinbioavailability and its use in studies carried out in South Africa andIndia (Ellard, G. A.; 1999; Int. J. Tuberc. Lung Dis.; November 3; 11;Suppl. 3: S284-5; McIleron, H. et al.; 1999; Int. J. Tuberc. Lung Dis.;November 3; 11; Suppl 3; S239-35; Panchagnula, R. et al.; 1999; Int. J.Tuberc. Lung Dis.; November 3; 11; Suppl 3; S336-42), high performanceliquid chromatographic methods for assaying of rifampicin, isoniazid andPyrazinamide (Smith, P. et al.; 1999; Int. J. Tuberc. Lung Dis.;November 3; 11; Suppl 3; S325-28) procedures for ensuring laboratoryproficiency for rifampicin bioavailability studies (Ellard, G. A.; 1999;Int. J. Tuberc. Lung Dis.; November 3; 11; Suppl 3; S343-46) improvedprocedure of dissolution testing of rifampicin in presence of isoniazid(Shishoo, C. J. et al.; 1999; Int. J. Pharm.; November 10; 190 (1):109-23) and a review of the pharmacology of rifampicin (Ellard, G. A. etal.; 1999; Int. J. Tuberc. Lung Dis.; November 3; 11 Suppl 3; S301-8:S317-21).

[0002] It has been reported that the poor absorption of rifampicin fromcombination products may be due to decomposition of the drug in acidicstomach conditions, which is accelerated in the presence of isoniazid(Shishoo, C. J. et al.; 1999; Int. J. Pharm.; November 10; 190 (1):109-23; Singh, S. et al.; 2000; Pharm. Pharmacol. Commun.; 6: 491-494).The mechanism of this degradation was proposed by Singh et al. (Singh,S. et al.; 2000; Pharm. Pharmacol. Commun.; 6: 405-410). Studiesrevealed that the decomposition of rifampicin in acidic conditions inthe absence of isoniazid stopped at the formation of 3-formylrifamycin,while the reaction in the presence of isoniazid proceeded to form ahydrazone between 3-formylrifamycin and isoniazid. Further, it wassuggested that once 3-formylrifamycin is formed, it interacts withisoniazid to form the hydrazone, through a fast second order reaction.As hydrazone are unstable in acid conditions, 3-formylrifamycin andisoniazid are regenerated in a reversible manner through a slower firstorder reaction. In this complex reaction process, rifampicin is furtherdegraded, while isoniazid is recovered.

[0003] Devani et al. (Devani, M. B. et al.; 1985; J. Pharm. Sci.; 74:427-432) has also discussed kinetics of hydrazone formation fromisoniazid in presence of reducing sugars.

[0004] None of the reports has suggested a pharmaceutical technologicalsolution to the above problem. The inventors after carefulexperimentation and expenditure of considerable amount of mentalfaculties and time have found a novel way to solve the bioavailabilityproblems of drugs in FDC tablets.

[0005] The invention described herein discloses compositions ofanti-tubercular drugs where attempts have been made to prevent the lossin bioavailability of rifampicin in presence of isoniazid.

[0006] During experimentation the inventors have found that thedegradation of rifampicin is pH dependent in presence of isoniazid. AtpH around 1 the degradation is minimum and increases abruptly as pHranges between 2 and 3. Thereafter, above pH 3 the degradation isminimal.

[0007] The pH of the gastric contents is normally between 1 and 3 whichresults in significant degradation of Rifampicin when administeredorally alongwith other anti-tubercular agents, in particular Isoniazid.

[0008] This problem has been solved by controlling the release ordissolution of both the drugs in such a way that the release takes placeat different locations inside the gastrointestinal tract withoutcompromising the total bioavailability of either of the drugs. It meansthat the two drugs i.e. rifampicin and isoniazid do not come in contactwith each other in solution state in the gastrointestinal tract therebypreventing the interaction. The composition may also include other knownanti-tubercular drugs like Ethambutol Hydrochloride and Pyrazinamide.

[0009] The site-specific release of active ingredients has been achievedby various techniques like

[0010] a) Controlling release of rifampicin and isoniazid at differentlocations in the gastrointestinal tract by use of pH sensitive materials

[0011] b) Controlling dissolution of drugs by forming barrier coatand/or matrix with pH insensitive materials such that the contact ofrifampicin and isoniazid in solution state is avoided.

[0012] c) Using different crystal forms of the drugs such that there issignificant difference in dissolution rate of the drugs.

[0013] d) Modifying the surfactant action of rifampicin with use ofmaterials like Methylpolysiloxane, natural and synthetic oils. Use ofsuch materials reduces the surfactant action with correspondingreduction in solubility of rifampicin.

[0014] Preferably the drug is modified such that the release takes placeat pH of approximately 5.0. At pH 5.0 the drug release takes place veryrapidly such that there is no loss of bioavailability. Whereas the otherdrug or drugs are released in the more acidic (pH 1.0-3.0) environmentof stomach.

[0015] Further, the invention discloses the Fixed Dose Combination ofanti-tuberculosis drugs in oral suspension form. Suspension type dosageforms are of particular importance for fixed dose combination where thetotal amount of active ingredients of a single dose becomes very high.Such high doses cannot be filled into hard or soft gelatin capsules.Even compressed tablets become too big and are very difficult toswallow.

[0016] It has surprisingly been found in the present invention that itis possible to conveniently administer such high dose combinations ofanti-tubercular drugs wherein one or more active ingredients may bepresent in extended or delayed release form, in the form of oralsuspension leading to no loss of bioavailability of any of the actives.This has been achieved by making molecular dispersion of Rifampicinand/or isoniazid having pH dependent delayed release characteristicseven when finely powdered. Such powders can be blended with other drugsand compressed into tablets or made into suspensions alongwith the otherdrugs. Another advantage is minimal increase in size of tablets which isserious problem for high dose drugs.

[0017] Further, the active ingredients may be in taste masked form. Suchdosage forms will be highly desirable for treatment of tuberculosis inmasses and reduction in the development of drug resistance whichcommonly occurs due to non compliance of existing type of dosage forms.

[0018] The active ingredients may be having barrier coating to preventdrug—drug/excipients interactions.

[0019] The suspension may be in ready-to-use form or to be reconstitutedbefore use. Preferably the ready-to-use suspensions will havenon-aqueous base/carrier. Suitable example of suspension bases includeglycols and glycol derivatives; Propylene carbonate; glycerol; oils ofanimal, vegetable or mineral origin; medium chain triglycerides;transesterification products of natural vegetable oils with alkylenepolyols; Esters of polyols with fatty acids.

[0020] Other ingredients of the suspension dosage form includessuspending agents, viscosity imparting agents, anti-caking agents,sweeteners, flavors, coloring agents and the like, known to personsskilled in the art.

[0021] The polymers used to modify the release of drugs may be natural,semi-synthetic, synthetic or man-modified. Suitable materials includecellulose and cellulose derivatives like microcrystalline cellulose,methyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose,hydroxypropyl cellulose, cellulose acetate phthalate, cellulose acetate,cellulose acetate butyrate, cellulose acetate propionate, celluloseacetate trimellitate, cellulose carboxymethyl ethers and their salts,hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcelluloseacetate succinate. Polyethylene; Polyquaternium-1; Polyvinyl acetate(homopolymer); Polyvinyl acetate phthalate; Propylene glycol alginate;PVM/MA copolymer; PVP/dimethiconylacrylate/polycarbamyl/polyglycolester;PVP/dimethylamino ethylmethacry-late copolymer;PVP/dimethylaminoethylmethacrylate/polycarbamyl polyglycol ester;PVP/polycarbamyl polyglycol ester; PVP/VA copolymer Lanolin and lanolinderivatives, buffers, lipophilic materials like, fats, fatty acidglycerides, oleic acid, cholesterol, transesterification products ofpolyols with fatty acids, glyceryl monostearate, stearic acid,paraffins, beeswax, carnauba wax, tribehenin. Polyalkylene polyols likepolyethylene glycols. Gelatin and gelatin derivatives. Alginates.Carbomers. Polycarbophils. Methacrylic acid copolymers. Carrageenans,pectins, chitosans, cyclodextrins, lecithins. Natural and synthetic gumscontaining galactomannans like xanthan gum, tragacanth, acacia, agar,guar gum, etc. Ion exchange resins like polacrilin pottasium, acrylicacid copolymers, sodium polystyrene sulphonate, polystyrene copolymersand the like.

[0022] Buffers like sodium dihydrogen orthophosphate, disodium hydrogenphosphate, dipotasium hydrogen phosphate, potassium dihydrogenorthophosphate, borate buffer, phthalate buffer, oxalate buffer and thelike.

[0023] In another embodiment of the invention, the active ingredient maybe present in micronized form to achieve faster absorption.Micronisation may be carried out by processes like air jet milling, ballmill and the like. The average particle size should be less than 5microns.

[0024] Further the invention also discloses use of bioavailabilityenhancers like piperine and its derivatives, Ayurvedic preparations liketrikatu alongwith the compositions of present invention may also help inincreasing bioavailability.

[0025] The invention is further described with the help of followingexamples which should not be construed as limiting the scope ofinvention:

[0026] 1. Microencapsulation of Rifampicin Cellulose Acetate Phthalate64 g Rifampicin 800 g Polyethylene Glycol 4000 6.4 g Water 1200 mlHydrochloric Acid 0.5 ml Dichloromethane 200 ml Isopropyl Alcohol 100 ml

[0027] Procedure

[0028] 1. Dissolve Cellulose Acetate Phthalate and Polyethylene Glycol4000 in Isopropyl Alcohol & Dichloromethane mixture

[0029] 2. Disperse rifampicin in water containing 0.5 ml of HydrochloricAcid to make a slurry and keep on a water bath at 50° C.

[0030] 3. Add CAP solution to the slurry with constant stirring.

[0031] 4. Filter off the microcapsules and dry them.

[0032] The above mentioned microcapsules of Rifampicin may be blendedwith other anti-tubercular drugs and suitable excipients to formulateinto tablets, capsules or suspension.

[0033] 2. Microencapsulation of Rifampicin Sodium Alginate 20 gRifampicin 100 g Calcium Chloride Solution 5% w/v Water 500 ml

[0034] Procedure

[0035] 1. Dissolve Sodium Alginate in Purified Water.

[0036] 2. Disperse rifampicin in above solution.

[0037] 3. Add the above suspension dropwise to Calcium Chloride Solutionwith constant stirring.

[0038] 5. Filter off the microcapsules and dry them.

[0039] The above mentioned microcapsules of Rifampicin may be blendedwith other anti-tubercular drugs and suitable excipients to formulateinto tablets, capsules or suspension.

[0040] 3. Preparation of Microcapsules of Rifampicin Rifampicin 100 gEthyl Cellulose M20 100 g Water 600 ml Dichloromethane 300 ml

[0041] Procedure

[0042] 1. Dissolve Ethylcellulose in dichloromethane.

[0043] 2. Disperse Rifampicin in water and keep in a water bath at 40°C.

[0044] 3. Add solution of Ethylcellulose to drug slurry with constantstirring.

[0045] 4. Filter off the microcapsules and wash with water and allow toair dry.

[0046] The above mentioned microcapsules of Rifampicin may be blendedwith other anti-tubercular drugs and suitable excipients to formulateinto tablets, capsules or suspension.

[0047] 4. Microspheres of Rifampicin Chitosan 500 mg Piuronic F68 2 gRifampicin 10 mg Sodium Tripolyphosphate (as 10% w/v solution in water)10 g Water 200 ml

[0048] Procedure

[0049] 1. Dissolve Chitosan in acetic acid containing Pluronic F-68 assurfactant.

[0050] 2. Add 10 mg drug into Chitosan solution. Then add SodiumTripolyphosphate dropwise with vigorous shaking. A cloudy suspension isformed as a result of crosslinking and precipitation of Chitosanmicrospheres.

[0051] 3. Centrifuge the microspheres at 3000 rpm for 10 minutes andwash the pellets twice with deionized distilled water and dry them.

[0052] The above mentioned microspheres of Rifampicin may be blendedwith other anti-tubercular drugs and suitable excipients to formulateinto tablets, capsules or suspension.

[0053] 5. Microspheres of Rifampicin Rifampicin 10 g Agar Agar 4 gCitric Acid 2 g Water 50 ml Polyvinyl Alcohol 15 g Ethanol 100 ml

[0054] Procedure

[0055] 1. Dissolve Citric Acid in Water and disperse Rifampicin, andAgar Agar in it with constant stirring.

[0056] 2. Meanwhile, dissolve Polyvinyl Alcohol in Ethanol.

[0057] 3. Add the aqueous solution to the alcoholic solution ofPolyvinyl Alcohol with constant stirring.

[0058] 4. Evaporate to dryness and separate the microspheres. Suchmicrospheres can be formulated in suspension type dosage form asexemplified below: Rifampicin 0.200 g (In microspheres form as perexample 5) Isoniazid (in taste masked form as per example 39) 0.300 gPyrazinamide 0.750 g Ethambutol Hydrochloride(in taste masked form asper example 28) 0.400 g Aspartame 0.025 g Labrafac PG (Gattefosse,France) 5.000 g Corn oil 3.000 g Butylated Hydroxyanisole 0.0015 gFlavour 0.097 g

[0059] Procedure

[0060] 1. Mix Labrafac PG and Corn oil and dissolve ButylatedHydroxyanisole in it with the aid of heat (40-50° C.).

[0061] 2. Then add Rifampicin, lsoniazid, Pyrazinamide, EthambutolHydrochloride, Flavour and Aspartame to the bulk with stirring.

[0062] 6. Bilayer Tablet Layer-I Rifampicin 0.225 g Hydroxypropyl methylCellulose Phthalate 0.050 g Isopropyl Alcohol 2.000 g Layer-II Isoniazid0.150 g Pyrazinamide 0.750 g Ethambutol Hydrochloride 0.400 g Starch0.075 g Water 0.500 g

[0063] Procedure

[0064] 1. Granulate Rifampicin with solution ofHydroxypropylmethylcellulose Phthalate in Isopropyl Alcohol and drythem.

[0065] 2. Separately, granulate Isoniazid, Pyrazinamide, EthambutolHydrochloride with Starch Paste in water and dry them.

[0066] 3. Compress the granules into Bilayered tablets on a rotapress.Isoniazid (Layer-II) is immediately released. Rifampicin layer isreleased in delayed form in pH 5.5 and above.

[0067] 7. Enteric Coated beads of Rifampicin Rifampicin 0.5 KgNon-pareil beads 1.2 Kg Polyvinyl Pyrrolidone 0.100 Kg Isopropyl Alcohol7.00 L Eudragit L100 0.40 Kg Acetone 6.00 L Water 1.00 L TriethylCitrate 0.04 Kg

[0068] Procedure

[0069] 1. Prepare The enteric coated beads of Rifampicin using fluid bedcoater.

[0070] 2. Spray dispersion of Rifampicin and Polyvinyl Pyrrolidone inIsopropyl Alcohol onto the fluidized non pareil beads.

[0071] 3. Spray dispersion of Eudragit L100 and Triethyl Citrate inwater/Acetone mixture on the rifampicin beads.

[0072] Such beads may be used in conjunction with other drugs to makeformulations as exemplified below: (i) Rifampicin 600 mg (In entericcoated bead form as per example 7) (ii) Isoniazid 150 mg

[0073] Mix (i) and (ii) and fill in hard gelatin capsules, or mix (i)and (ii) with suitable lubricants and diluent like lactose,microcrystalline cellulose and compress into tablets or fill in hardcarpsules.

[0074] 8. Rifampicin Granules (Delayed Release) Rifampicin 9.00 KgEudragit L100 (Rohm Pharma, Germany) 1.00 Kg Acetone 3.0 L Water 0.5 L

[0075] Procedure

[0076] 1. Dissolve Eudragit L 100 in mixture of acetone and water.

[0077] 2. Granulate Rifampicin in a rapid mixer granulator with theabove solution. Sift the wet mass through 10 mesh screen and dry.

[0078] 3. After drying the granules, sift the granules through 30 meshscreen. Such granules may be added to a oral suspension or capsule orcompressed into tablets alongwith other active agents and excipients.

[0079] The above mentioned granules of Rifampicin may be blended withother anti-tubercular drugs and suitable excipients to formulate intotablets, capsules or suspension.

[0080] 9. Molecular Dispersion of Rifampicin with Enteric (DelayedRelease) Effect Rifampicin 9.00 Kg Eudragit L100 (Rohm Pharma, Germany)0.50 Kg Cellulose Acetate Phthalate 1.00 Kg Isopropyl Alcohol 5.0 LMethylene chloride 10.0 L

[0081] Procedure

[0082] 1. Dissolve Eudragit L 100 and Cellulose Acetate Phthlate inmixture of Isopropyl Alcohol and Methylene Chloride separately. Mix boththe solutions.

[0083] 2. Dissolve Rifampicin in Methylene Chloride and add to the abovesolution and mix for one hour.

[0084] 3. Evaporate the solvents on a water bath and pass the residuethrough a sieve of mesh size 100.

[0085] The above mentioned powder of Rifampicin has almost no release inacid stage i.e. pH 1-3 for upto 2 hours. Whereas above pH 5.5 more than85% of drug is released in about 45 minutes. This powder may be blendedwith other anti-tubercular drugs and suitable excipients to formulateinto tablets, capsules or suspension. Upon compression, there is nochange in release of rifampicin during acid stage.

[0086] 10. Molecular Dispersion of Rifampicin with Enteric (DelayedRelease) Effect Rifampicin 8.00 Kg Eudragit L100 (Rohm Pharma, Germany)0.50 Kg Polyvinyl Acetate Phthalate 0.75 Kg Isopropyl Alcohol 4.0 LDichloromethane 8.0 L

[0087] Procedure

[0088] 1. Dissolve Eudragit L 100 and Polyvinyl Acetate Phthalate are inmixture of Isopropyl Alcohol and Dichloromethane separately. Mix boththe solutions.

[0089] 2. Dissolve Rifampicin was dissolved in Dichloromethane and addto the above solution and mix for one hour.

[0090] 3. Evaporate the solvents on a water bath and pass the through asieve of mesh size 100.

[0091] The above mentioned powder of Rifampicin may be blended withother anti-tubercular drugs and suitable excipients to formulate intotablets, capsules or suspension.

[0092] 11. Molecular Dispersion of Rifampicin with Enteric (DelayedRelease) Effect Rifampicin 2.00 Kg Shellac 0.10 Kg Isopropyl Alcohol 1.0L Methylene Chloride 2.0 L

[0093] Procedure

[0094] 1. Dissolve Shellac in a mixture of Isopropyl Alcohol andMethylene Chloride separately.

[0095] 2. Dissolve Rifampicin in Methylene chloride and add to the abovesolution and mix for two hours.

[0096] 3. Evaporate the solvents on a water bath and pass the residuethrough a sieve of mesh size 100.

[0097] The above mentioned powder of Rifampicin may be blended withother anti-tubercular drugs and suitable excipients to formulate intotablets, capsules or suspension.

[0098] 12. Rifampicin Granules (Delayed Release) Rifampicin 2.00 KgEudragit L 30D 0.20 Kg Purified Water 0.50 L

[0099] Procedure

[0100] 1. Dilute Eudragit L 30 D with Purified Water.

[0101] 2. Granulate Rifampicin with the above solution in a mass mixerfor 1.5-2.0 h.

[0102] 3. Pass the wet mass through multimill and dry the granules.

[0103] An oral suspension using such granules is described below:

[0104] Oral Suspension Rifampicin 225 mg (In delayed release granuleform as per example 12) Isoniazid 150 mg (In taste masked form for tastemasking as per example 39) Ethambutol Hydrochloride 400 mg (inion-exchange complexed form for taste masking as per example 28)Pyrazinamide 750 mg Colloidal Silicon Dioxide 100 mg Aspartame 20 mgFlavour q.s Medium Chain Triglyceride q.s to 10 ml

[0105] Procedure

[0106] Disperse Colloidal Silicon Dioxide, Aspartame in Medium chaintriglyceride. Add rifampicin granules, Isoniazid, EthambutolHydrochloride and Pyrazinamide and flavour with stirring.

[0107] 13. FDC Formulation Containing Piperine as Absorption EnhancerRifampicin 225 mg (In delayed release granule form as per example 12)Piperine 60 mg Isoniazid 150 mg (In taste masked form for taste maskingas per example 39) Ethambutol Hydrochloride 400 mg (in ion-exchangecomplexed form for taste masking as per example 28) Pyrazinamide 750 mgColloidal Silicon Dioxide 100 mg Aspartame 20 mg Flavour q.s MediumChain Triglyceride q.s to 10 ml

[0108] Procedure

[0109] Disperse Colloidal Silicon Dioxide, Aspartame in Medium chaintriglyceride. Add rifampicin granules, Piperine, Isoniazid, Ethambutoland Pyrazinamide and flavour with stirring.

[0110] 14. pH sensitive fast release granules of Rifampicin CoreRifampicin 20 parts Low substituted Hydroxypropyl Cellulose 52 partsLactose 13 parts Hydroxypropyl Cellulose 5 parts Alcohol (Ethanol 95%v/v) 20 parts Film Eudragit L 100 5.5 parts Isopropyl Alcohol 60.2 partsAcetone 33.5 parts Dibutyl Phthalate 0.8 parts

[0111] Procedure

[0112] 1. Mix Rifampicin, Low substituted Hydroxypropyl Cellulose,Lactose.

[0113] 2. Granulate the above bulk with alcoholic solution ofHydroxypropyl Cellulose.

[0114] 3. Dry the granules and sift through mesh 60.

[0115] 4. Coat the granules with enteric film forming solution ofEudragit L 100 and Dibutyl Phthalate in Isopropyl Alcohol and Acetoneusing fluid bed coater.

[0116] Such granules may be used to make capsules, tablets or oralsuspension.

[0117] 15. Millispheres of Rifampicin Phase-I Rifampicin 10 g SodiumAlginate 20 g Water 90 g Phase-II Chitosan 5 g Calcium Chloride 5 gWater 200 ml

[0118] Prepare Phase-I solution by dispersing Rifampicin and SodiumAlginate in Water. Dissolve Chitosan, Calcium Chloride in water toprepare Phase-II. Add Phase-I dropwise with stirring to Phase-II. Softmillispheres of rifampicin are formed. Separate by filteration and dryunder vacuum.

[0119] Such millispheres may be used to formulate oral suspension dosageform alongwith other anti-tubercular agents.

[0120] 16. Rifampicin in Lipophilic Matrix Rifampicin 5.0 Kg GlycerylMonostearate 2.0 Kg Poloxamer 188 0.1 Kg Lactose 2 Kg Ethyl Cellulose0.5 Kg Alcohol (Ethanol 95% v/v) 2.0 L

[0121] Procedure

[0122] 1. Dissolve Glyceryl Monostearate and Poloxamer in Alcohol andheat up to 70° C. so as to obtain a clear solution.

[0123] 2. Add drug to the bulk and cool.

[0124] 3. Evaporate the alcohol and granulate the residue with Lactoseas diluents and Ethyl Cellulose as binder.

[0125] Such granules may be used to formulate a tablet, capsule, dosageform or oral suspension dosage form alongwith other anti-tubercularagents.

[0126] 17. Rifampicin in Carbomer Matrix Rifampicin 5.0 Kg Carbomer(Carbopol 934P, BF Goodrich) 1.0 Kg Lactose 5.0 Kg Ethyl Cellulose 0.5Kg Acetone 2.0 L Alcohol (Ethanol 95% v/v) 10.0 L Water 5.0 L

[0127] Procedure

[0128] 1. Dissolve the drug in alcohol and Carbopol in water. Mix boththe solution and keep aside for one hour.

[0129] 2. Evaporate the solvents and pulverised the mass into powder andgranulate with Lactose as diluent and Ethyl Cellulose in Acetone asbinder.

[0130] Such granules may be used to formulate a tablet, capsule, dosageform or oral suspension dosage form alongwith other anti-tubercularagents.

[0131] 18. Mesosomes of Rifampicin Rifampicin 2.0 Kg GlycerylMonostearate 1.0 Kg Palmitic Acid 0.5 Kg Tween 60 0.1 Kg Water 5.0 L

[0132] Melt Glyceryl Monostearate and Palmitic Acid in a water bath anddisperse drug in it Pour the molten mass to hot purified watercontaining Tween 60 under stirring. Then add this to ice chilled waterwith continuous stirring. Filter the mesosomes and air dry them.

[0133] The above mentioned mesosomes of rifampicin may be blended withanti tubercular drugs and suitable excipients to formulate into tablets,capsules or suspensions

[0134] 19. Tablet-in-Tablet Formulation (Rifampicin in Delayed ReleaseForm) Core tablet Per tablet Rifampicin 225 mg Starch 20 mg Lactose 28mg Water — Magnesium Stearate 10 mg Sodium Lauryl sulphate 10 mg SodiumStarch Glycollate 30 mg

[0135] Pass Rifampicin and Lactose through sieve and granulate withStarch Paste and pass through multimill. Dry the granules at 50° to 60°C. and pass through sieve of mesh size 18. Pass Sodium StarchGlycollate, Sodium Lauryl Sulphate and Magnesium Stearate through sieveof mesh size 40 and mix with the dried granules and compress.

[0136] Enteric Coating of Rifampicin Tablets (Batch Size 2.0 Kg)Eudragit L 100 88.00 g Purified Talc 20.00 g Triethyl Citrate 18.00 gDichloromethane 1.30 L Isopropyl Alcohol 0.60 L

[0137] Dissolve Eudragit L 100 in Isopropyl Alcohol and dichloromethanemixture. Add Triethyl Citrate and Talc to the above bulk and mix for 45minutes. Coat the tablets to a weight build up of 6-8% w/w.

[0138] Outer Tablet Pyrazinamide 750 mg Ethambutol Hydrochloride 400 mgIsoniazid 150 mg Magnesium Stearate 10 mg Sodium Starch Glycollate 30 mgLactose 65 mg Povidone 50 mg Purified Water —

[0139] Pass Pyrazinamide, Ethambutol Hydrochloride, Isoniazid andlactose through a sieve and granulate with Povidone solution in water.Pass the wet mass through multimill and dry the granules 50-60° C. Passdried granules through sieve of mesh size 16. Pass Magnesium Stearateand Sodium Starch Glycollate through sieve of mesh size 60 and mix withdried granules. Compress into tablets alongwith the Rifampicin entericcoated tablets in between.

[0140] Film Coating of Outer Tablets (Batch Size 2.0 Kg) Hypromellose40.00 g Purified Talc 2.00 g Polyethylene Glycol 400 8.00 g TitaniumDioxide 2.00 g Colour q.s. Dichloromethane 0.66 L Isopropyl Alcohol 0.33L

[0141] Dissolve Hypromellose in Isopropyl Alcohol and Dichloromethanemixture. Add Polyethylene Glycol 400, Titanium Dioxide, Purified Talcand colour to the above bulk and mix for 45 minutes. Coat the tablets toa weight build up of 3-4% w/w.

[0142] 20. Tablet-in-Tablet Formulation (Isoniazid in Delayed ReleaseForm) Isoniazid 150 mg Lactose 30 mg Starch 5 mg Water — MagnesiumStearate 3 mg Purified Talc 3 mg

[0143] Pass Isoniazid and Lactose through sieve and granulate withStarch paste and pass through multimill. Dry the granules at 50° to 60°C. and pass through sieve of mesh size 18. Pass Magnesium Stearate andTalc through sieve of mesh size 60 and mix with the dried granules andcompress.

[0144] Enteric Coating of Isoniazid Tablets (Batch Size 2.0 Kg)Hydroxypropylmethyl Cellulose Phthlate 80.00 g Purified Talc 25.00 gDibutyl Sebacate 15.00 g Dichloromethane 1.30 L Isopropyl Alcohol 0.60 L

[0145] Dissolve Hydroxypropylmethyl Cellulose Phthlate in IsopropylAlcohol and Dichloromethane mixture. Add Dibutyl Sebacate and Talc tothe above bulk and mix for 45 minutes. Coat the tablets to a weightbuild up of 4-6% w/w.

[0146] Outer Tablet Pyrazinamide 750 mg Ethambutol Hydrochloride 400 mgRifampicin 225 mg Lactose 70 mg Magnesium Stearate 10 mg Sodium StarchGlycollate 15 mg Povidone 30 mg Purified Water —

[0147] Pass Pyrazinamide, Ethambutol Hydrochloride, Rifampicin andLactose through a sieve and granulate with Povidone solution in water.Pass the wet mass through multimill and dry the granules at 50-60° C.Pass the dried granules through sieve of mesh size 16. Pass MagnesiumStearate and Sodium Starch Glycollate through sieve of mesh size 60 andmix with dried granules. Compress the tablets alongwith the Isoniazidenteric coated tablets in between.

[0148] Film Coating of Outer Tablets (Batch Size 2.0 Kg) Hypromellose40.00 g Purified Talc 2.00 g Polyethylene Glycol 400 8.00 g TitaniumDioxide 2.00 g Colour q.s. Dichloromethane 0.66 L Isopropyl Alcohol 0.33L

[0149] Dissolve Hypromellose in Isopropyl Alcohol and Dichloromethanemixture. Add Polyethylene Glycol 400, Titanium Dioxide, Purified Talcand colour to the above bulk and mix for 45 minutes. Coat the tablets toa weight build up of 3-4% w/w.

[0150] 21. Tablet Formulation Containing Isoniazid in Delayed ReleaseForm Core tablet Per tablet Isoniazid 150 mg Lactose 30 mg Eudragit L 30D (Rohm Pharma, Germany) 50 mg Purified Water —

[0151] Pass Isoniazid and Lactose through sieve and granulate withaqueous dispersion of diluted Eudragit L 30 D in a mass mixer for atleast 2 hours. Pass the granules through sieve and dry them.

[0152] Outer Tablet Isoniazid Enteric Coated equivalent to 230 mgIsoniazid 150 mg Ethambutol Hydrochloride 400 mg Pyrazinamide 750 mgRifampicin 225 mg Lactose 20 mg Magnesium Stearate 10 mg Sodium StarchGlycollate 35 mg Povidone 30 mg Purified Water —

[0153] Pass Pyrazinamide, Ethambutol Hydrochloride, Rifampicin andLactose through a sieve and granulate with Povidone solution in water.Pass the wet mass through multimill and dry the granules at 50-60° C.Pass the dried granules through sieve of mesh size 16. Mix MagnesiumStearate, Sodium Starch Glycollate and Isoniazid granules with abovegranules and compress.

[0154] Film Coating of Tablets (Batch Size 2.0 Kg) Hypromellose 40.00 gPurified Talc 2.00 g Polyethylene Glycol 400 8.00 g Titanium Dioxide2.00 g Colour q.s. Dichloromethane 0.66 L Isopropyl Alcohol 0.33 L

[0155] Dissolve Hypromellose in Isopropyl Alcohol and Dichloromethanemixture. Add Polyethylene Glycol 400, Titanium Dioxide, Purified Taleand colour to the above bulk and mix for 45 minutes. Coat the tablets toa weight build up of 3-4% w/w.

[0156] 22. Molecular Dispersion of Isoniazid with Enteric (DelayedRelease) Effect Isoniazid 10.00 Kg Eudragit L100 (Rohm Pharma, Germany)2.00 Kg Isopropyl Alcohol 5.0 L Alcohol (Ethanol 95% v/v) 15.0 L

[0157] Dissolve Eudragit L 100 in Isopropyl Alcohol. Dissolve Isoniazidin Alcohol and add to the above solution and mix for one hour. Evaporatethe solvents on a water bath and pass the residue through a sieve ofmesh size 100.

[0158] The above powder may be used to make capsules, tablets or oralsuspension.

[0159] 23. Molecular Dispersion of Isoniazid with Enteric (DelayedRelease) Effect Isoniazid 8.00 Kg Eudragit L100 (Rohm Pharma, Germany)1.00 Kg Polyvinyl Acetate Phthalate 0.75 Kg Isopropyl Alcohol 4.0 LAlcohol (Ethanol 95 % v/v) 15.0 L

[0160] Dissolve Eudragit L 100 and Polyvinyl Acetate Phthalate inIsopropyl Alcohol separately. Mix both the solutions and dissolveIsoniazid in Alcohol and add to the above solution and mix for one hour.Evaporate the solvents on a water bath and pass the residue through asieve of mesh size 100.

[0161] The above powder may be used to make capsules, tablets or oralsuspension.

[0162] 24. Molecular Dispersion of Isoniazid with Enteric (DelayedRelease) Effect Isoniazid 2.00 Kg Shellac 0.10 Kg Isopropyl Alcohol 1.0L Alcohol (Ethanol 95 % v/v) 5.0 L

[0163] Dissolve Shellac in a Isopropyl Alcohol. Dissolve Isoniazid inAlcohol and add to the above solution and mix for two hours. Evaporatethe solvents on a water bath and pass the residue through a sieve ofmesh size 100.

[0164] An oral suspension using above molecular dispersion is describedbelow:

[0165] Oral Suspension Isoniazid 150 mg (In delayed release moleculardispersion form as per example 23) Rifampicin 225 mg EthambutolHydrochloride 400 mg (in ion-exchange complexed form for taste maskingas per example 28) Pyrazinamide 750 mg Colloidal Silicon Dioxide 100 mgAspartame 20 mg Flavour q.s Medium Chain Triglyceride q.s to 10 ml

[0166] Disperse Colloidal Silicon Dioxide, Aspartame in Medium chainTriglyceride. Add Isoniazid powder, Rifampicin, Ethambutol Hydrochlorideand Pyrazinamide and flavour with stirring.

[0167] 26. Enteric Coated Beads of Isoniazid Isoniazid 1.0 Kg Non-pareilbeads 3.0 Kg Polyvinyl Pyrrolidone 0.20 Kg Isopropyl Alcohol 14.00 LEudragit L100 0.80 Kg Acetone 12.00 L Water 2.00 L Triethyl Citrate 0.10Kg

[0168] Procedure

[0169] The enteric coated beads of Isoniazid are manufactured usingfluid bed coater. Spray dispersion of Isoniazid and PolyvinylPyrrolidone in Isopropyl Alcohol onto the fluidized non pareil beads.Further coat dispersion of Eudragit L100 and Triethyl Citrate inwater/Acetone mixture on the Isoniazid beads.

[0170] Such beads may be used in conjunction with other drugs to makeformulation as examplified below: (i) Isoniazid 150 mg (In entericcoated bead form as per example 25) (ii) Rifampicin 600 mg

[0171] Mix (i) and (ii) and fill in hard gelatin capsules, or mix (i)and (ii) with suitable lubricants and diluent like lactose,microcrystalline cellulose and compress into tablets

[0172] 26. Isoniazid in Lipophilic Matrix Isoniazid 5.0 Kg GlycerylMonostearate 2.0 Kg Poloxamer 188 0.1 Kg Lactose 2 Kg Ethyl Cellulose1.0 Kg Alcohol (Ethanol 95% v/v) 10.0 L

[0173] Dissolve Glyceryl Monostearate and Poloxamer in Alcohol and heatup to 70° C. so as to obtain a clear solution. Add drug to the bulk andcool. Evaporate the Alcohol and granulate the mixture with Lactose asdiluents and Ethyl Cellulose as binder.

[0174] The above mentioned granules of Isoniazid may be blended withother anti-tubercular drugs and suitable excipients to formulate intotablets, capsules or suspension.

[0175] 27. Bilayer Tablet Containing Isoniazid in Extended Release FormLayer-I Isoniazid 0.150 g Hydroxypropylmethyl Cellulose K4M 0.050 gIsopropyl Alcohol 2.000 g Layer-II Rifampicin 0.225 g EthambutolHydrochloride 0.400 g Pyrazinamide 0.750 g Starch 0.075 g Water 0.500 g

[0176] Granulate Isoniazid with solution of HydroxypropylmethylCellulose K4M in Isopropyl Alcohol and dry. Granulate Rifampicin,Ethambutol Hydrochloride and Pyrazinamide with Starch paste in water anddry. Compress into bilayered tablets on a rotapress. Rifampicin(Layer-II) is immediately released. Isoniazid layer is released indelayed form.

[0177] 28. Ethambutol Hydrochloride in Taste Masked Form UsingComplexation Ethambutol Hydrochloride 1.0 Kg Polystyrene Copolymer 2.0Kg Water 5.0 L

[0178] Disperse Polystyrene copolymer in Water and add EthambutolHydrochloride to it with constant stirring. Continue stirring for twohours and filter the complex and dry.

[0179] The above complex may be included in a tablet, capsule orsuspension dosage form for taste masked and delayed release Isoniazidsuspension containing other antitubercular drugs.

[0180] 29. Tablet-in-Tablet Formulation (Rifapentine in Delayed ReleaseForm) Core tablet: Per tablet Rifapentine 150 mg MicrocrystallineCellulose 75 mg Starch 10 mg Water — Disodium Edetate 3 mg MagnesiumStearate 5 mg Purified Talc 2 mg Sodium Lauryl Sulphate 5 mg

[0181] Pass Rifapentine and Microcrystalline Cellulose through sieve andgranulate the mass with Starch paste and pass through multimill. Dry thegranules at 50° to 60° C. and pass through sieve of mesh size 18. PassMagnesium Stearate, Disodium Edetate, Sodium Lauryl Sulphate andPurified Talc through sieve of mesh size 60 and mix with the driedgranules and compress.

[0182] Enteric Coating of Rifapentine Tablets (Batch Size 2.0 Kg)Cellulose Acetate Phthlate 85.00 g Purified Talc 20.00 g PolyethyleneGlycol 400 10.00 g Dichloromethane 1.33 L Isopropyl Alcohol 0.66 L

[0183] Dissolve Cellulose Acetate Phthlate in Isopropyl Alcohol andDichloromethane mixture. Add Polyethylene Glycol 400 and Talc to theabove bulk and mix for 45 minutes. Coat the tablets to a weight build upof 4-6% w/w. Pyrazinamide 750 mg Ethambutol Hydrochloride 400 mgIsoniazid 150 mg Lactose 60 mg Magnesium Stearate 20 mg Sodium StarchGlycollate 30 mg Starch 20 mg Purified Talc 5 mg Purified Water —

[0184] Pass Pyrazinamide, Ethambutol Hydrochloride, Isoniazid andLactose through a sieve and granulate with Starch Paste prepared inPurified Water. Pass the wet mass through multimill and dry the granulesat 50-60° C. Pass the dried granules through sieve of mesh size 16. PassMagnesium Stearate, Purified Talc and Sodium Starch Glycollate throughsieve of mesh size 60 and mix with dried granules. Compress the tabletsalongwith the Rifapentine enteric coated tablets in between.

[0185] Film Coating of Outer Tablets (Batch Size 2.0 Kg) Hypromellose40.00 g Purified Talc 2.00 g Polyethylene Glycol 400 8.00 g TitaniumDioxide 2.00 g Colour q.s. Dichloromethane 0.66 L Isopropyl Alcohol 0.33L

[0186] Dissolve Hypromellose in Isopropyl Alcohol and Dichloromethanemixture. Add Polyethylene Glycol 400, Titanium Dioxide, Purified Talcand colour to the above bulk and mix for 45 minutes. Coat the tablets toa weight build up of 3-4% w/w.

[0187] 30. Effervescent Tablet/Granules (Rifampicin in Delayed ReleaseForm). Rifampicin Enteric Coated Granules 225 mg Equivalent toRifampicin (from example no. 8) Pyrazinamide 750 mg Isoniazid 150 mgEthambutol Hydrochloride 400 mg Anhydrous Citric Acid 340 mg SodiumBicarbonate 360 mg Anhydrous Sodium Carbonate 20 mg Povidone 50 mgPolyethylene Glycol 6000 25 mg Sodium Benzoate 20 mg Aspartame 20 mgMagnesium Stearate 7.5 mg Sodium Lauryl Sulphate 2.5 mg Flavour 25 mgIsopropyl Alcohol — Dichloromethane —

[0188] Pass Pyrazinamide, Ethambutol Hydrochloride, Isoniazid through asieve of mesh size 40. Pass Anhydrous Citric Acid, Sodium Bicarbonateand Anhydrous Sodium Carbonate through sieve of mesh size 100 and mixwith the above bulk. Dissolve Povidone in Isopropyl Alcohol andDichloromethane mixture and granulate the bulk with binder solution andpass the wet mass through multimill and dry the granules. Pass the driedgranules through sieve of mesh size 16. Pass Magnesium Stearate,Polyethylene Glycol 6000, Aspartame, Sodium Benzoate, Sodium LaurylSulphate and flavour through sieve and mix with dried granules.

[0189] The above effervescent granules can be dispensed in apouch/sachets or in a tablet dosage form. All the processing is carriedin dehumidified conditions at relative humidity not more than 20% andtemperature not more than 25° C.

[0190] 31. Buffered Tablets Containing Rifampicin in Delayed ReleaseForm Rifampicin delayed release granules 225 mg equivalent to Rifampicin(from example no. 8) Pyrazinamide 750 mg Isoniazid 150 mg EthambutolHydrochloride 400 mg Lactose 22.5 mg Starch 30 mg Magnesium Stearate 7.5mg Sodium Starch Glycollate 30 mg Sodium Carbonate 100 mg Purified Water—

[0191] Pass Pyrazinamide, Ethambutol Hydrochloride, Isoniazid andLactose through a sieve of mesh size 40. Granulate the above bulk withStarch paste containing water and pass the wet mass through multimilland dry the granules. Pass Magnesium Stearate, Sodium Starch Glycollateand Sodium Carbonate through sieve and mix with dried granules,rifampicin enteric coated granules and compress. Film Coating of tablets(Batch Size 2.0 Kg) Hypromellose 40.00 g Purified Talc 2.00 gPolyethylene Glycol 400 8.00 g Titanium Dioxide 2.00 g Colour q.s.Dichloromethane 0.66 L Isopropyl Alcohol 0.33 L

[0192] Dissolve Hypromellose in Isopropyl Alcohol and Dichloromethanemixture. Add Polyethylene Glycol 400, Titanium Dioxide, Purified Talcand colour to the above bulk and mix for 45 minutes. Coat the tablets toa weight build up of 3-4% w/w.

[0193] 32. Hard Gelatin Capsule Formulation Containing Isoniazid inDelayed Release Form. Per Capsule Isoniazid Enteric Coated tablets 200mg ≅ Tab. (example no. 20) Rifampicin (Compacted) 225 mg Sodium LaurylSulphate  3 mg

[0194] Pass Rifampicin through sieve of mesh size 22 and mix with theSodium Lauryl Sulphate previously passed through sieve of mesh size 40.Fill 228 mg of above powder and one Isoniazid enteric coated tablet ineach empty hard gelatin capsules size “0”.

[0195] 33. Molecular Dispersion of Rifabutin with Enteric (DelayedRelease) Effect Rifabutin 10.00 Kg Eudragit L100 (Rohm Pharma, Germany)2.50 Kg Isopropyl Alcohol 6.0 L Dichloromethane 17.0 L

[0196] Dissolve Eudragit L 100 in a mixture of Isopropyl Alcohol andDichloromethane. Disslove Rifabutin in Dichloromethane and add to theabove solution and mix for one hour. Evaporate the solvents on a waterbath and pass the residue through a sieve of mesh size 100.

[0197] The above mentioned powder of Rifabutin may be blended with otheranti-tubercular drugs and suitable excipients to formulate into tablets,capsules or suspension.

[0198] 34. Tablet Formulation Containing Rifabutin in Delayed ReleaseForm Per tablet Rifabutin 150 mg (In delayed release moleculardispersion form as per example 33) Isoniazid 150 mg EthambutolHydrochloride 400 mg Pyrazinamide 750 mg Lactose 135 mg MagnesiumStearate 20 mg Sodium Starch Glycollate 30 mg Starch 30 mg Purified Talc5 mg

[0199] Pass Pyrazinamide, Ethambutol Hydrochloride, Isoniazid andLactose through a sieve and granulate with Starch Paste prepared inPurified Water. Pass the wet mass through multimill and dry the granulesat 50-60° C. Pass the dried granules through sieve of mesh size 16. MixMagnesium Stearate, Sodium Starch Glycollate, Purified Talc andRifabutin delayed release powder with dried granules and compress.

[0200] Film Coating of Tablets (Batch Size 2.0 Kg) HydroxypropylMethycellulose 40.00 g Purified Talc 2.00 g Polyethylene Glycol 400 8.00g Titanium Dioxide 2.00 g Colour q.s. Dichloromethane 0.66 L IsopropylAlcohol 0.33 L

[0201] Dissolve Hydrxypropylmethylcellulose in Isopropyl Alcohol andDichloromethane mixture. Add Polyethylene Glycol 400, Titanium Dioxide,Purified Talc and colour to the above bulk and mix for 45 minutes. Coatthe tablets to a weight build up of 3-4% w/w.

[0202] 36. Powder for Reconstitution Containing Isoniazid in DelayedRelease Form. Isoniazid 150 mg (In delayed released molecular dispersionform as per example 22) Rifampicin 225 mg Ethambutol Hydrochloride 400mg (In ion exchange complexed form for taste masking as per example 28)Pyrazinamide 750 mg Methyl Hydroxybenzoate 5 mg Sodium Metabisulphite 10mg Sweetening Agent q.s. Xanthan Gum 20 mg Flavour q.s.

[0203] Pass Pyrazinamide, Ethambutol Hydrochloride, Isoniazid delayedrelease powder, Rifampicin, Methyl Hydroxybenzoate, and SodiumMetabisulphite through sieve of mesh size 60. Pass Xanthan Gum andSweetening Agent through a sieve of mesh size 100. Mix both the bulksand fill in amber coloured glass bottles.

[0204] 36. Powder for Reconstitution Containing Rifampicin in DelayedRelease Form. Rifampicin in delayed release molecular 225 mg dispersionform equivalent to Rifampicin (as per example 9) Isoniazid 150 mg (intaste masked form as per example 39) Ethambutol Hydrochloride 400 mg (Inion exchange complexed form for taste masking as per example 28)Pyrazinamide 750 mg Methyl Hydroxybenzoate 5 mg Sodium Metabisulphite 10mg Sweetening Agent q.s. Xanthan Gum 20 mg Flavour q.s.

[0205] Pass Pyrazinamide, Ethambutol Hydrochloride, Isoniazid,Rifampicin delayed release powder, Methyl Hydroxybenzoate, and SodiumMetabisulphite through sieve of mesh size 60. Pass Xanthan gum andSweetening Agent through a sieve of mesh size 100 and mix both the bulksand fill in amber coloured glass bottles.

[0206] 37. An Anti Tubercular Formulation in Kit Form. The kit contains(A) One tablet of Isoniazid 150 mg (Enteric coated) (B) One tabletcontaining Rifampicin, Ethambutol Hydrochloride and Pyrazinamide (Filmcoated)

[0207] (A) Isoniazid Tablets 150 mg (Enteric coated) Per tabletIsoniazid 150 mg Lactose 30 mg Starch 5 mg Water — Magnesium Stearate 3mg Purified Talc 3 mg

[0208] Pass Isoniazid and Lactose through sieve and granulate the masswith Starch paste and pass through multimill. Dry the granules at 50° to60° C. and pass through sieve of mesh size 18. Pass Magnesium Stearateand Talc through sieve of mesh size 60 and mix with the dried granulesand compress.

[0209] Enteric Coating of Isoniazid Tablets (Batch Size 2.0 Kg) EudragitL 100 80.00 g Purified Talc 25.00 g Triethyl Citrate 15.00 gDichloromethane 1.30 L Isopropyl Alcohol 0.60 L

[0210] Dissolve Eudragit L 100 in Isopropyl Alcohol and Dichloromethanemixture. Add Triethyl Citrate and Talc to the above bulk and mix for 45minutes. Coat the tablets to a weight build up of 4-6% w/w.

[0211] (B) Rifampicin, Ethambutol Hydrochloride and Pyrazinamide Tablets(Film Coated) Per Tablet Pyrazinamide 750 mg Ethambutol Hydrochloride400 mg Rifampicin 225 mg Lactose 50 mg Magnesium Stearate 15 mg Talc 6mg Starch 19 mg Crospovidone 35 mg Purified Water —

[0212] Pass Pyrazinamide, Ethambutol Hydrochloride, Rifampicin andLactose through a sieve and granulate with Starch paste prepared inPurified Water. Pass the wet mass through multimill and dry the granulesat 50-60° C. Pass dried granules through sieve of mesh size 16. PassMagnesium Stearate, Purified Talc and Crospovidone through sieve of meshsize 60 and mix with dried granules and compress. Film Coating oftablets (Batch Size 2.0 Kg) Hypromellose 40.00 g Purified Talc 2.00 gPolyethylene Glycol 400 8.00 g Titanium Dioxide 2.00 g Colour q.s.Dichloromethane 0.66 L Isopropyl Alcohol 0.33 L

[0213] Dissolve Hypromellose in Isopropyl Alcohol and Dichloromethanemixture. Add Polyethylene Glycol 400, Titanium Dioxide, Purified Talcand colour to the above bulk and mix for 45 minutes. Coat the tablets toa weight build up of 3-4% w/w.

[0214] 38. An Anti Tubercular Formulation in Kit Form. The kit contains(A) One tablet of Rifampicin 150 mg (Enteric coated). (B) One tabletcontaining Isoniazid, Ethambutol Hydrochloride and Pyrazinamide (Filmcoated).

[0215] (A) Rifampicin Tablets 150 mg (Enteric Coated) Per tabletRifampicin 225 mg Microcrystalline Cellulose 55 mg Starch 10 mg Water —Magnesium Stearate 5 mg Sodium Lauryl Sulphate 5 mg

[0216] Pass Rifampicin and Microcrystalline Cellulose through sieve andgranulate the mass with Starch paste and pass through multimill. Dry thegranules at 50° to 60° C. and pass through sieve of mesh size 18. PassMagnesium Stearate and Sodium Lauryl Sulphate through sieve of mesh size60 and mix with the dried granules and compress.

[0217] Enteric Coating of Rifampicin Tablets (Batch Size 2.0 Kg)Eudragit L 100 80.00 g Purified Talc 25.00 g Triethyl Citrate 15.00 gDichloromethane 1.30 L Isopropyl Alcohol 0.60 L

[0218] Dissolve Eudragit L 100 in a Isopropyl Alcohol andDichloromethane mixture. Add Triethyl Citrate and Talc to the above bulkand mix for 45 minutes. Coat the tablets to a weight build up of 4-6%w/w.

[0219] (B) Isoniazid, Ethambutol Hydrochloride and Pyrazinamide Tablets(Film Coated) Per Tablet Pyrazinamide 750 mg Ethambutol Hydrochloride400 mg Isoniazid 150 mg Magnesium Stearate 15 mg Talc 6 mg Starch 35 mgSodium Starch Glycollate 35 mg Purified Water —

[0220] Pass Pyrazinamide, Ethambutol Hydrochloride and Isoniazid througha sieve and granulate with Starch paste prepared in Purified Water. Passthe wet mass was passed through multimill and dry the granules at 50-60°C. Pass the dried granules through sieve of mesh size 16. Pass MagnesiumStearate, Purified Talc and Sodium Starch Glycollate through sieve ofmesh size 60 and mix with dried granules and compress.

[0221] Film Coating of Tablets (Batch Size 2.0 Kg) HydroxypropylMethylcellulose 40.00 g Purified Talc 2.00 g Polyethylene Glycol 4008.00 g Titanium Dioxide 2.00 g Colour q.s. Dichloromethane 0.66 LIsopropyl Alcohol 0.33 L

[0222] Dissolve Hydroxypropyl Methylcellulose in Isopropyl Alcohol andDichloromethane mixture. Add Polyethylene Glycol 400, Titanium Dioxide,Purified Talc and colour to the above bulk and mix for 45 minutes. Coatthe tablets to a weight build up of 3-4% w/w.

[0223] 39. Isoniazid in Taste Masked Form Using Complexation Isoniazid1.0 Kg Polystyrene Copolymer 2.0 Kg Water 5.0 L

[0224] Disperse Polystyrene copolymer in Water and add Isoniazid to itwith constant stirring. Continue stirring for two hours and filter thecomplex and dry.

[0225] The above complex may be included in a tablet, capsule orsuspension dosage form for taste masked and delayed release Isoniazidsuspension containing other antitubercular drugs.

[0226] 40. Microemulsion Formulation of Rifampicin and Other TubercularDrugs. Per Tablet Rifampicin 150 mg Pyrazinamide 250 mg EthambutolHydrochloride 267 mg Isoniazid 100 mg Poloxamer 188 25 mg Vitamin EPolyethylene Glycol Succinate 20 mg Hydrogenated vegetable Oil 20 mgMagnesium Stearate 15 mg Talc 6 mg Starch 35 mg Sodium Starch Glycollate35 mg Purified Water —

[0227] Pass Pyrazinamide, Ethambutol Hydrochloride, Rifampicin andIsoniazid through a sieve and granulate with Starch paste containingPoloxamer 188, Vitamin E Polyethylene Glycol Succinate and Hydrogenatedvegetable oil. Pass the wet mass was passed through multimill and drythe granules at 50-60° C. Pass the dried granules through sieve of meshsize 16. Pass Magnesium Stearate, Purified Talc and Sodium StarchGlycollate through sieve of mesh size 60 and mix with dried granules andcompress.

[0228] Such tablets on dilution with water gives a microemulsion.

[0229] 41. Vesicular Carriers for Rifampicin Rifampicin 500 mgChloroform q.s. Cholesterol 49 mg Polysorbate 80 35 mg DistearylPhosphatidyl Choline 7 mg Dichloromethane 10 ml Calcium Chloride (25 mMsolution) 10 ml

[0230] Dissolve Rifampicin in minimum volume of Chloroform and addCholesterol, Polysorbate 80 and Distearyl Phosphatidyl Choline to it.Add Dichloromethane, 2 ml of calcium Chloride solution. Sonicate for 2hours or till a milky emulsion is formed and evaporate the solvent layerunder controlled conditions of temperature and pressure on a rotaevaporator till a semisolid viscous liquid is obtained. Now addremaining amount of Calcium Chloride solution and evaporate the solventson a rota evaporator for overnight and collect the vesicular carriers.

[0231] Such carriers can be incorporated into a tablet, capsule orliquid dosage form.

[0232] 42. Tablet Containing Rifampicin in Molecular Dispersion (inDelayed Release) Form. Per Tablet Rifampicin in delayed releasemolecular dispersion 225 mg Form equivalent to Rifampicin (as perexample no. 9) Pyrazinamide 750 mg Ethambutol Hydrochloride 400 mgIsoniazid 150 mg Lactose 60 mg Magnesium Stearate 20 mg Sodium StarchGlycollate 30 mg Starch 20 mg Purified Talc 5 mg Purified Water —

[0233] Pass Pyrazinamide, Ethambutol Hydrochloride, Isoniazid andLactose through a sieve and granulate with Starch Paste prepared inPurified Water. Pass the wet mass through multimill and dry the granulesat 50-60° C. Pass the dried granules through sieve of mesh size 16. PassMagnesium Stearate, Purified Talc and Sodium Starch

[0234] Glycollate through sieve of mesh size 60 and mix with driedgranules and rifampicin delayed release powder. Compress the blend intotablets.

[0235] Film Coating of Tablets (Batch Size 2.0 Kg) Hypromellose 40.00 gPurified Talc 2.00 g Polyethylene Glycol 400 8.00 g Titanium Dioxide2.00 g Colour q.s. Dichloromethane 0.66 L Isopropyl Alcohol 0.33 L

[0236] Dissolve Hypromellose in Isopropyl Alcohol and Dichloromethanemixture. Add Polyethylene Glycol 400, Titanium Dioxide, Purified Talcand colour to the above bulk and mix for 45 minutes. Coat the tablets toa weight build up of 3-4% w/w.

[0237] 43. Tablet Containing Isoniazid in Molecular Dispersion (inDelayed Release) Form. Per Tablet Isoniazid in delayed release moleculardispersion 150 mg form equivalent to Isoniazid (as per example no. 23)Pyrazinamide 750 mg Ethambutol Hydrochloride 400 mg Rifampicin 225 mgLactose 60 mg Magnesium Stearate 20 mg Sodium Starch Glycollate 30 mgStarch 20 mg Purified Talc 5 mg Purified Water —

[0238] Pass Pyrazinamide, Ethambutol Hydrochloride, Rifampicin andLactose through a sieve and granulate with Starch Paste prepared inPurified Water. Pass the wet mass through multimill and dry the granulesat 50-60° C. Pass the dried granules through sieve of mesh size 16. PassMagnesium Stearate, Purified Talc and Sodium Starch Glycollate throughsieve of mesh size 60 and mix with dried granules and isoniazid delayedrelease powder. Compress the blend into tablets.

[0239] Film Coating of Tablets (Batch Size 2.0 Kg) Hypromellose 40.00 gPurified Talc 2.00 g Polyethylene Glycol 400 8.00 g Titanium Dioxide2.00 g Colour q.s. Dichioromethane 0.66 L Isopropyl Alcohol 0.33 L

[0240] Dissolve Hypromellose in Isopropyl Alcohol and Dichloromethanemixture. Add Polyethylene Glycol 400, Titanium Dioxide, Purified Talcand colour to the above bulk and mix for 45 minutes. Coat the tablets toa weight build up of 3-4% w/w.

1. A pharmaceutical composition of anti tubercular drugs for oral usecomprising Rifampicin and/or Isoniazid, wherein the bioavailability ofRifampicin and/or other drugs is enhanced.
 2. A pharmaceuticalcomposition of anti tubercular drugs for oral use comprising Rifampicinand/or Isoniazid wherein, more preferably, the bioavailability ofRifampicin is enhanced by preventing its degradation caused by presenceof Isoniazid.
 3. A composition as claimed in claim 1 wherein Rifampicinand Isoniazid do not come in contact with each other in solution state.4. A composition as claimed in claim 1 wherein Rifampicin and Isoniaziddo not come in contact with each other in solution state at pH between 1and
 4. 5. A composition as claimed in claim 1 wherein Rifampicin ispresent in delayed release and/or extended release form such thatminimal amount of Rifampicin is dissolved between pH 1 and
 4. 6. Acomposition as claimed in claim 1 wherein Isoniazid is present indelayed release and/or extended release form such that minimal amount ofdrug is dissolved between pH 1 and
 4. 7. A composition as claimed in anyof the preceding claims wherein delayed release of Rifampicin and/orIsoniazid is achieved by treating the drugs with pH sensitive polymerscomprising Cellulose Acetate Phthalate, Hydroxypropyl MethylcellulosePhthalate, Polyvinyl Acetate Phthalate, Hydroxypropyl MethycelluloseAcid Succinate, Alginic Acid, Methacrylic Acid Polymers, Carbomers,Polacrillin Potassium and Chitosan.
 8. A composition as claimed in claim1 to 7 wherein Rifampicin and/or Isoniazid is present in form ofmolecular dispersion along with a pH sensitive polymer resulting indelayed release of drug.
 9. A composition as claimed in any of thepreceding claims wherein extended release of Rifampicin and/or Isoniazidis achieved by treating the drugs with pH independent polymerscomprising Cellulose, Hydroxypropyl Methylcellulose, HydroxypropylCellulose, Hydroxyethyl Cellulose, Ethyl Cellulose; Natural Gums likeXanthan gum, Karaya Gum, Guar gum, Tragacanth and Acacia.
 10. Acomposition as claimed in any of the preceding claims which is dispensedin kit form wherein the drugs are present in individual unit dosageforms.
 11. A composition as claimed in any of the preceding claimswherein Rifampicin and/or Isoniazid is present in micronized form.
 12. Acomposition as claimed in any of the preceding claims comprising crystalor polymorphic forms of Rifampicin and/or Isoniazid having reducedsolubility between pH 1 and
 4. 13. A composition as claimed in any ofthe preceding claims which comprises buffers to raise the pH of gastriccontents beyond
 3. 14. A composition as claimed in any of the precedingclaims which comprises bioavailability enhancing agents like Piperineand Ayurvedic formulation like Trikatu.
 15. A composition as claimed inany of the preceding claims which is amenable to high speed, low costmanufacturing and also easy to administer such as in the form oftablets, capsules, suspension, pastilles, jellies and powder forreconstitution.
 16. A composition as claimed in claim 15 wherein thetablets may be film coated tablets, compression coated tablets orbilayer tablets.
 17. A composition as claimed in claim 1 wherein theanti-tubercular drugs are present in taste neutralized form.
 18. Aprocess for the preparation of a pharmaceutical composition as claimedin claim 1 which comprises enhancing the bioavailability of Rifampicinand/or Isoniazid.
 19. A process as claimed in claim 18 wherein, morepreferably, the bioavailability of Rifampicin is enhanced by preventingits degradation caused by presence of Isoniazid.
 20. A process asclaimed in claim 18 wherein Rifampicin and Isoniazid do not come incontact with each other in solution state.
 21. A process as claimed inclaim 18 wherein the drugs Rifampicin and/or Isoniazid are made into‘delayed release form’ or extended release form'.
 22. A process asclaimed in claim 21 wherein the drugs Rifampicin and/or Isoniazid aremade into ‘delayed release form’ or extended release form' bymicrosphere formation by conventional polymers by the conventionaltechniques.
 23. A process as claimed in claims 18 to 22 wherein delayedrelease of Rifampicin and/or Isoniazid is achieved by treating the drugswith pH sensitive polymers comprising cellulose acetate phthalate,Hydroxypropyl methylcellulose phthalate, Polyvinyl acetate phthlate,Hydroxypropyl methyl cellulose acid succinate, alginic acid, Methacrylicacid polymers, Carbomers, Polacrillin and Chitosan.
 24. A process asclaimed in claims 18 to 23 wherein extended release of Rifampicin and/orIsoniazid is achieved by treating the said drugs with pH independentpolymers comprising Cellulose, Hydroxypropyl methyl cellulose,Hydroxyethyl cellulose, Ethyl cellulose, Natural gums like Xanthan gum,Karaya gum; Guar gum, Tragacanth and Acacia.
 25. A process as claimed inclaims 18 to 24 wherein the drugs Rifampicin and/or Isoniazid arepresent in micronized form.
 26. A process as claimed in claims 18 to 25wherein the drugs Rifampicin and/or Isoniazid are present in tasteneutralized form.
 27. A process as claimed in claims 18 to 26 whereincrystal or polymorphic forms of Rifampicin and/or Isoniazid havingreduced solubility between pH 1 and 4 are used.
 28. A process as claimedin claims 18 to 27 wherein conventional buffers are added to thecomposition to raise the pH of gastric contents beyond
 3. 29. A processas claimed in any of the preceeding claims wherein bioavailabilityenhancing agents like Piperine and Ayurvedic formulation like Trikatuare added to the composition.
 30. A process as claimed in any of thepreceeding claims wherein the composition prepared is formed intotablets, capsules, suspensions, pastilles, jellies or powder forreconstitution by known methods.
 31. A process for the preparation ofanti tubercular drugs composition for oral use substantially as hereindescribed and illustrated by the examples herein.
 32. A pharmaceuticalcomposition of anti tubercular drugs for oral use substantially asherein described and illustrated by the examples herein.